肝细胞癌多基因甲基化异常及其临床意义

目的 探讨肝细胞癌中多基因甲基化异常的发生率,研究肝细胞癌中多基因甲基化异常的临床意义.方法 收集60例肝细胞癌及相应的癌旁组织、16例肝炎后肝硬化组织、5例慢性肝炎和5例正常肝组织,筛选消化道肿瘤中APC、RASSF1A、p16、GSTP1、MGMT、DAPK、SOCS-1和RIZ18个甲基化异常频率高的肿瘤抑制基因,应用甲基化特异件聚合酶链反应(MSP)检测8个肿瘤抑制基因在所有标本中的甲基化状态.比较不同基因甲基化与非甲基化肝细胞癌患者的临床病理特征和生存情况.结果 肝细胞癌组织中,RASSF1A、APC、GSTP1、p16、RIZ1和MGMT基因的甲基化率分别为95.0%、90.0%、73.3%、65.0%、61.6%和60.0%,均高于相应的癌旁组织(均P＜0.05);癌旁组织中,MGMT、GSTP1和RIZ1基因的甲基化率分别为41.6%、40.0%和25.0%,均高于肝硬化组织(均P＜0.05).p16基因甲基化的肝细胞癌患者的平均年龄大于非甲基化者;巨块性肝细胞癌中,MGMT基因甲基化者的比例高于非甲基化者;MGMT基基甲基化者的无瘤生存期短于非甲基化者.结论 不同基因在肝细胞癌、癌旁和肝硬化组织中的甲皋化率差异显示了肝细胞癌发生中渐进的表观遗传学改变;GSTP1、RIZ1和MGMT基因的甲基化异常具有肿瘤风险评估和早期诊断价值,而MGMT基因的甲基化异常同时具有预后评估价值.

Aberrant methylation of multiple genes and its clinical implication in hepatocellular carcinoma

Objective To investigate the methylation frequencies of multiple tumor suppressor genes (TSGs)in hepatocellular carcinoma(HCC)and the clinical implication of aberrant DNA methylation in molecular carcinogenesis of HCC.Methods Sixty samples of HCC and the paired adjacent Iiver tissue.16 samples from post-hepatitis cirrhotic livers.5 from livers with chronic hepatitis and 5 from normallivers were collected.Eight TSGs frequently silenced by hypermethylation of their promoters in various typos of digestive tumors were selected,including APC,RASSF1A,p16,GSTP1,MGMT,DAPK,SOCS-1 and RIZ1.The status of promoter methylation in these 8 genes was investigated using methylation-specific polymeric chain reaction.The clinicopathological data of HCC were also analyzed in order to evaluate the clinical implication of aberrant methylation in HCC.Results Methylation of the 8 TSGs was quite frequent in HCC,with a methylation rate of 95.0%in RASSF1A,90.0%in APC,73.3%in GSTP1,65.0%in p16.61.6%in RIZ1 and 60.0%in MGMT.Methylation of the 6 genes was more frequent in HCC than that in adjacent tissues(P＜0.05).The methylation rate of MGMT.GSTP1 and RIZ1 in the adjacent tissues was 41.6%,40.0%and 25.0%,respectively,significantly higher than that in cirrhotic liver(P＜0.05).p16 methylation was more frequently observed in HCC in elderly patients.The frequency of MGMT methylaiton was;tended to be higher in giant HCC than that in the other types of HCC.Patients with MGMT methylation in the tumor were found to have a shorter disease free Survival.Conclusion Different frequency of methylation in hepatocellular carcinomas.adiacent liver tissues and cirrhotic Iivers implies that epigenetic alteration in the hepatocellular carcinogenesis may be a gradually progressive process.Methylation status of MCMT,CSTP1 and RIZ1 may be promising in risk assessment of hepatocellular carcinoma and in early diagnosis.Furthermore,MGMT methylation might be also used as a potential prognostic biomarker for hcpatocellular carcinoma patients.